Chronic physical
exercise or physical training (PT) has been widely used in the last years with
therapeutic and preventive purposes in a series of pathophysiological conditions,
including cardiovascular disease. Besides the cardiovascular benefits, PT seems
capable to modulate in pathological conditions, at the presence of an abnormal
inflammatory response, including over expression of proinflammatory cytokines
through a neuro-immune-endocrine interaction. Nowadays chronic heart failure
(CHF) is reviewed as the consequence of an interplay of hemodynamic, neurohormonal,
immunological and endocrine mechanisms. This abnormal inflammatory response,
including the over expression of proinflammatory cytokines may be proposed as
responsible for the progression and clinical deterioration in CHF. Tumor necrosis
factor-a (TNF-a) is the
main proinflammatory cytokines involved in the inflammatory cascade implicated
in the pathophysiological of CHF. PT may improve exercise performance by modifying
the inflammatory status, as well as by allowing reversing the inflammation-induced
harmful effects on the cardiovascular system, and that PT may represent an important
immunomodulatory option that may be possible to intervene in the progression
of the disease.

Chronic physical
exercise or physical training (PT) has been widely used in the last years with
therapeutic and preventive purposes in a series of pathophysiological conditions,
including cardiovascular disease(1-4), among others. The potential
beneficial effects of physical exercise chronically performed in several distinct
situations, in other words, in pathological conditions or with the objective
of improving the athletic performance seem to be associated with the fact that
physical exercises promote adaptations in all compartments of the animal body(5).
These alterations may be characterized as an organic and functional reorganization
in function of inside and outside requirements. The persistent alterations on
the structure or function are particularly associated to responses to the stimulus
generated by physical exercises systematically performed along time(6).

The physical training program is composed of:
constant-overload repetitive phases, phases with increases on the
overload (overreaching), phases of maintenance of this increase
(overtraining) and recovery phases(7). The overload
phases are characterized by the difference between the total
amount of overload (volume x intensity x density) and the
recovery time between training sessions. Thus, the recovery phase
between training sessions is necessary and enables the
restoration and the improvement on the exercise performance,
metabolism and homeostasis along time. When the recovery time is
sufficient, this situation is characterized as overreaching. On
the other hand, if the recovery time is not sufficient and if it
lasts for a long period, a state of chronic alterations
(molecular, biochemical and regulatory) may be obtained, leading
to disorders that involve well-being, increases on the incidence
of diseases and impaired performance during exercise. The balance
between the training specificity, physiological stressors and
others and the recovery process determine the results or the
positive adaptations of a given period of physical
training(7,8).

Thus, Lehmann et
al.(9) proposed a biphasic model of the training overload response
predominantly involving: 1  peripheral mechanisms at initial overload
phases and 2  central mechanisms at more intense overload phases or overtraining.
This means that muscular lesions and the metabolic demand are mainly involved
in the acute response to training and the chronic alterations lead not only
to alterations on the tissue metabolism, somatic differentiation, body composition
and functionality of organs, but also to central regulatory dysfunctions(10).

The hypothalamus plays a central integrating role of all
afferent signalization to the brain and also an important role in
the regulation to the central responses to stress and physical
training(7). These interactions include afferent
information from the autonomous nervous system, direct metabolic
effects, hormones and cytokines, as well as information from
upper cerebral centers, demonstrating a complex interaction
involving the bidirectional communication between neuroendocrine
and immune systems(11-13).

Physical training and the immune system

During the last twenty years, many efforts have been made in
order to understand the mechanisms responsible for the
interaction between physical exercise and the immune system and
to study the effects of the physical training on
health(5,14-17).

Currently, the fact that the physical training improves
physical capacities such as motor strength, aerobic resistance,
among others is well established, thus contributing for a better
physical and psychological condition(18).
Epidemiological evidences have demonstrated a positive
correlation between the practice of physical activity and the
decrease on the mortality rate incidence of several types of
cancers and other chronic diseases(15,16,19-21).

According to Pedersen & Hoffman-Goetz(16), the
increasing number of studies on physical exercise and immune
system has demonstrated an important modulating effect of the
function of cells from the immune system possibly on the system
as a whole. These effects are regulated by several factors
including the exercise-induced release of proinflammatory
cytokines, hormones and hemodynamic effects that lead to a cells
redistribution. The nature of this interaction is complex and not
fully understood. Some alterations observed are: modifications on
the expression of adhesion molecules, selective recruitment of
mature lymphocytes and impairment of the mitosis and apoptosis
processes in the immune system cells.

These alterations,
however, have raised the interest of using the chronic physical exercise or
the physical training performed at moderate intensities (< 60% O2max)
as alternative non-pharmacological therapeutics in some pathological situations(15,16),
where at this intensity, epidemiological evidences demonstrate higher infections
resistance on the upper respiratory tract(22,23).

Some hypotheses
have been proposed in order to explain the relation between the regular practice
of physical exercise and the susceptibility of acquiring infections both among
athletes and among inactive individuals. Nieman(15) proposed a "J"
shape curve model that describes a relation between the amount of exercise and
the incidence of infections of the upper respiratory tract. Pedersen & Ullm(24)
proposed the "open window" model, period in which after intense (> 75% O2max)
and long-duration (> 1 hour) exercise, a high risk of infection due to the
post-exercise immunosuppression is observed.

The relevant point of both hypotheses is that both suggest
that moderate intensity exercises present an stimulating effect
on the immune function, also presenting practical implications
when applied conjointly to pathological situations such as
cancer(19), in infectious conditions such as
poliomyelitis, myocardial diseases, HIV and
aging(15-17,21).

In this context, two research lines have been currently
proposed in the attempt of understanding the mechanisms that
support these hypotheses in order to establish a connection
between exercise and the immune system: a metabolic approach
involving the glutamine metabolism(25), and other,
that considers alterations on the neuroendocrine milieu as
an immunomodulation mechanism(26).

Alterations on the immune system in the chronic heart
failure

The acute myocardial infarction is associated with an
inflammatory reaction, which is prerequisite for cicatrization
processes(27). The heart ischemia situation causes
alterations on the mechanisms of defense against the formation of
oxygen reactive species, as the production of free radicals is
increased(28). These latter potentially wound the
cardiac myocyte and the vascular cells and may be involved in the
mediation of the inflammatory cascade through the induction of
cytokines(27).

After these initial
occurrences, the response to the myocardial infarction is associated with the
coordinated activation of a series of cytokines and the activation of genes
for the synthesis of adhesion molecules. On the other hand, the mechanisms responsible
for the activation of the cytokines cascade have only been investigated in recent
years. Initial studies conducted by Frangogiannis et al.(29)
indicate an important role the mast cells play in the mediation of the cytokines
cascade and release. These cells are an important source of TNF-a,
chemokines and growth factors. The constitutive presence of TNF-a
in heart mast cells in canines led these authors to postulate that the mast
cells-derived TNF-a may be released following the
myocardial ischemia, representing an important source of this cytokine in the
initial phases of the inflammatory process.

Myocardial dysfunction and heart failure are expressions that
correspond to the drop on the heart mechanical performance that
may be slight (dysfunction) or intense (failure). In patients
with moderate or relatively intense myocardial dysfunction and
those with heart failure, the damage on the myocardial function
may be detected by means of studies on the cardiac pump total
function, where lower degrees can only be detected by more
specific indexes of myocardial contractility. The dysfunction or
advanced failure conditions, the cardiac pump overall function
(and the cardiac debt in rest) may be maintained within normality
levels through compensatory mechanisms such as the increase on
the ventricular filling, the increase on the pre-load (dilation)
and/or the cardiac hypertrophy. In the myocardial infarction, the
heart failure primarily occurs due to the loss of cells and
secondly due to the chronic hypertrophy associated to the
cicatrization or to the hypertrophic dysfunction. Finally, the
heart failure associated to mechanical abnormalities that may be
present ends up by leading to damages on the systolic function of
the pump with sufficient intensity to determinate the heart pump
overall failure(30,31).

Thus, the myocardial infarction chronic alterations and hence
the heart failure may be considered as an event that induces to
structural, hemodynamic and functional generalized
alterations(30-35), and both chronic and acute forms
are considered as a stress condition to the organism. On the
other hand, in the last years these alterations have been
considered as a progressive and chronic disorder that affects
different metabolic and physiologic features. Recently, this
condition has been reconsidered as an interaction between
hemodynamic, neurohormonal, endocrine and immunological
mechanisms that would have adaptive effects for the organism to
compensate the loss of the heart capacity to pump blood
adequately(36).

The comprehension of the pathophysiologic aspects of the
chronic myocardial infarction and hence the chronic heart failure
(CHF) is a hard task especially due to two reasons: Firstly, this
condition may have several causes such as heart ischemic
diseases, myopathic dilated cardiomyopathy and valvular
dysfunction that compose most cases. Second, the CHF is a
multi-systemic disorder that affects not only the cardiovascular
system but also the muscle-skeletal, renal, neuroendocrine and
immune systems(28,36,37). In past, the myocardial
chronic failure pathogenesis was understood and explained through
a cardiovascular model. Currently, clinical and experimental
evidences demonstrate that this hypothesis is unsatisfactory to
explain symptoms experienced by patients in full, as well as
peripheral manifestations of the disease(28,38),
suggesting that the immune and the neurohormonal systems may play
an important role in this process(28,37).

According to Shan
et al.(39), the CHF is a state of immune activation with proinflammatory
cytokines that contributes for manifestations both of central and peripheral
orders. Thus, it has been proposed that this abnormal inflammatory response,
including the high expression of proinflammatory cytokines, soluble adhesion
molecules and chemoattractive factors may be responsible for the development
and clinical deterioration in the CHF(38,40). In this context, the
main cytokines involved in the pathophysiologic role of the chronic heart failure
are the tumor necrosis factor-alpha (TNF--a) and
the interleukine-6 (IL-6).

The TNF-a
was originally identified by its powerful cytotoxic effect against tumoral cells.
It deals about a trimeric polypeptide (17 KDa) mainly produced by activated
monocytes and macrophages and by other cells such as lymphocytes, fibroblasts
and, neutrophils, smooth muscle and mast cells(38-41). This cytokine
may act in almost all types of nucleated cells through an interaction with membrane
receptors or as a soluble molecule, both biologically active(38,40,42).
Moreover, the heart myocyte from adult mammals is able to produce TNF-a
after extracellular stimuli such as endotoxines, hypoxia or the increase on
the mechanical stress(43).

The TNF-a
acts at cells level through two types of receptors: type I (TNFI) and type II
(TNFII), and the presence of these two types of receptors in the heart myocyte
of humans was recently demonstrated(44). The fragments of the extracellular
domains of both TNF-a receptors (types I and II)
may be released from the cell membrane and detected in their soluble form (sTNFRI
and sTNFRII) in urine and plasma(45). These soluble proteins act
as regulatory agents of its biological activity. In physiological concentrations,
the sTNFR act as a "slow-release supply", thus increasing the half-lives of
this cytokine(38,40,41). When present in high concentrations, as
in individuals with severe heart failure (classes III and IV), the sTNFR may
inhibit the pathologic progression of the TNF-a,
thus acting as a TNF-a anti-molecule. One suggests
that the sTNFR quantification is underlying in order to evaluate the TNF-a
activation in individuals with heart failure(38,41).

The effect of TNF-a
on the cardiac function depends on the amount and duration on the gene expression
of this cytokine. This increase, when acute, may have an adaptive effect on
the heart for different stress forms, and when chronic, it may perform opposite
effect, impairing the adaptive processes and producing cardiac discompensation,
what suggests that this cytokine plays dual role(40,41).

High TNF-a
concentrations have been found in some patients with CHF, being particularly
associated with a higher severity of the clinical aspects in the heart failure(41,46).
TNF-a may be the main causal agent of a series of
metabolic dysfunctions present in individuals with heart failure such as: high
metabolic rate(36,38), decrease on the blood flow to peripheral tissues(40)
and alteration on the protein and lipid metabolism(41). Besides its
known thermogenic effect, high concentrations of this cytokine may be associated
with the elevation on the insulin plasma concentrations, abnormalities on the
steroids hormones metabolism, growth hormones(36), dysfunction of
the left ventricle(41,47) and exercise intolerance(40,47-49).
Recent studies demonstrated the presence of high TNF-a
concentrations in individuals with cardiac cachexia, and this cytokine is an
important weight loss predictor(37).

However, in relation
to the mechanisms responsible for inducing this increase on the TNF-a
production, not much is known and thus, some hypotheses have been proposed.
It is well known that activated monocytes and macrophages are the main source
of TNF-a(38-41,47), and that an increase
on the prostaglandin E2, observed in patients with CHF could stimulate
macrophages to produce TNF-a(41,50). Other
evidences indicate that in the CHF condition, this cytokine is activated regardless
the inflammatory situation and the cause of the disease, suggesting that the
increase on the TNF-a production is more associated
to the presence of CHF-imposed limitations instead of being the causative agent
of this condition(41,45). Thus, the mechanisms that modulate the
TNF-a production in this condition are not fully
known and, on the other hand, it seems to play a complex role as a communication
"link" between several regulatory systems(38,41,47).

Effects of the physical training on the chronic heart
failure

A metanalysis on the trial of patients after myocardial
infarction demonstrated a reduction of 25% on the total number of
deaths among patients submitted to aerobic physical training
program(4).

The physical training performed through aerobic exercises is
currently considered as the base of heart rehabilitation programs
and an important non-pharmacological way of treatment and allows
minimizing the risk factors that predispose individuals to
cardiovascular diseases(1,3). It is generally employed
as a multidimensional rehabilitation program that begins within
two to six weeks after discharge from hospital, with exercise
sessions such as walks, runs, swimming, among
others(3,4,46).

The final objectives of these programs are to increase the
physical and psychological capacities of the individual, to
control the cardiorespiratory symptoms, to decrease the risk of
sudden death and the relapse of infarctions in such way to
reestablish a normal daily life routine, especially activities
interrupted due to the disease(4). On the other hand,
patients with chronic obstructive pulmonary disease, class IV
functional heart failure, cachexia, complex ventricular
arrhythmias and osteomyoarticular pathologies cannot be submitted
to regular practice of physical activities, and the utilization
of physical training programs is inadequate in these
cases(3,4).

The potential benefits
of the aerobic training performed at intensities from light to moderate (40-85%
of the O2max) 3 to 5 days a week during
20-60 minutes(1,3) in post-infarction patients have been extensively
reported(1,3,4,46). The light to moderate aerobic training program
contributes to the improvement on the cardiovascular system with lower heart
rate and blood pressure within the same work overload(3,4,46). This
leads to a peripheral adaptation in the high-density and low-density cholesterol
balance (HDL/LDL) and to effects on the angina threshold. Beneficial effects
on the carbohydrate metabolism, blood viscosity and reduction on the total body
mass have also been described(4).

Patients with cardiovascular
diseases submitted to light to moderate intensity aerobic training present enhanced
O2 uptake maximum capacity (O2max.),
particularly when previously sedentary. This improvement seems to be initially
due to the peripheral adaptations on the active skeletal musculature in function
of an increase on the O2 venous-arterial difference(3).
Another important effect is the higher myocardial O2 supply due to
the increase on the blood flow to the coronary arteries and the reduction both
initial and recurrent on the risk of myocardial infarction(3,4).

The light to moderate intensity aerobic training may also
increase the oxygen supply to the myocardium due to the increase
on the blood flow through the coronary artery. These adaptations
include an increase on the myocardial capillary density,
enlargement of the main coronary arteries and enhance on the
development of collateral vessels in the presence of a
progressive or chronic occlusion of the coronary
artery(3).

Beneficial effects on the carbohydrate metabolism, blood
viscosity and reduction on the total body mass have also been
described(4).

Besides the cardiovascular benefits induced both by
adaptations in function of the heart's pumping and by peripheral
adaptations, the physical training seems to have a modular effect
in pathological conditions that present an abnormal chronic
inflammatory condition, especially due to the high expression of
proinflammatory cytokines, soluble adhesion molecules and
chemoattractive factors(40,49,52).

Batista Jr.(52)
using Wistar rats with chronic myocardial infarction demonstrated a chronic
increase on the chemotaxis index and on the production of TNF-a through macrophages
from the peritoneal cavity of these animals, demonstrating a chronic activation
of these cells. On the other hand, the moderate aerobic training in treadmill
(60% of the O2 peak) with 10-week duration
5 times a week during 1 hour a day was capable to revert this situation. Adamapoulus
et al.(40) demonstrated a reduction on the plasma concentration
of peripheral markers of inflammation (cellular-1 soluble adhesion molecule,
vascular cell-1 soluble molecule, chemoattractive protein for macrophages 
1) after 12 weeks of aerobic training in cycle ergometer (70-80% of the HR max)
5 times a week during 1 hour a day in patients with moderate to severe heart
failure (New York Heart Association, functional class II-III), suggesting a
correlation between the enhanced exercise tolerance and the attenuation of the
inflammatory process due to a possible reversion on the harmful effects caused
by the endothelial dysfunction presented in the heart failure condition. However,
a significant correlation cannot establish a cause-effect relation, and other
mechanisms have been proposed in order to explain the beneficial effects obtained
through physical training programs in individuals with heart failure. The reduction
on the plasma TNF-a concentration, IL-6 and its respective
soluble receptors has also been demonstrated in individuals with chronic heart
failure submitted to an aerobic training program(48), suggesting
an attenuation on the chronic inflammatory condition mediated by a regulation
on the peripheral inflammatory response(40,48,52). Similarly, the
utilization of a 4-month physical training program with aerobic exercises in
cycle ergometer (90% of the anaerobic threshold-I) performed 3 times a week
during 20 minutes along with endurance exercises (50% of the MR and 9 exercises
per session) during 30 minutes presented a reduction on the sTNFR I and II concentrations
in patients with CHF, suggesting possible effects of the simultaneous use of
aerobic and endurance exercises on the attenuation of the inflammatory condition(49).

Alterations on
the neuro-immune-endocrine axis(5,7,52) and metabolic abnormalities
on the muscle-skeletal(40) have been proposed in order to explain
alterations that lead to exercise intolerance as well as possible mediators
of their beneficial effects. Thus, the role of several regulatory systems that
result in metabolic abnormalities mediated through inflammatory and hormonal
dysfunctions has been demonstrated in individuals with CHF, and currently this
condition has been considered as a chronic degenerative disease as result of
a multi-systemic interaction, in other words, an interface between hemodynamic,
neurohormonal and immunological variables and metabolic dysfunctions. In this
condition, the scientific evidences recently observed suggest that inflammatory
mediators such as proinflammatory cytokines play important role both in the
pathogenesis and in the development of the CHF syndromes. Thus, moderate physical
training programs lasting from 3 to 6 months with 3 to 5 weekly sessions during
1 hour, besides providing a positive effect on the cardio-circulatory variables,
already well-established in literature, would act as important positive immune-modulator,
reverting, even partly, the inflammatory alterations as result of the CHF condition,
reinforcing its non-pharmacological intervention role.

CONCLUSION

Interestingly,
the adaptations to physical training demonstrated in individuals with chronic
heart failure promoted a decrease on the hemodynamic and metabolic overload
both in the cardiovascular and in the muscle-skeletal systems and modified inflammatory
parameters, leading to a decrease on the peripheral inflammatory markers concentration,
especially on the production of cytokine, remarkably the tumoral necrosis factor.
This cytokine is important during the establishment and development of the inflammatory
process following the development of the chronic heart failure, vital for the
recovery, even partial, of the cardiac muscle functions, but mainly, harmful,
when present in high concentrations in the chronic phase of the pathology. Moreover,
it becomes evident that this chronic inflammatory condition plays important
role on the decrease on the capacity of performing physical exercises, an important
characteristic of this syndrome. Thus, considering the modulating effect of
the moderate physical exercise on the TNF-a production
in patients with CHF, a larger number of researches becomes necessary in order
to evaluate possible alterations on the temporal production of other proinflammatory
cytokines and researches aimed at evaluating the ideal type and form of exercise
to be prescribed to this specific population, thus allowing the physician to
prescribe regular physical exercises as part of clinical treatment of the CHF.

All the authors
declared there is not any potential conflict of interests regarding this article.